The broad, long-term goal of this proposal is to elucidate the organization of neural systems that determine mood and affect. The primary objective of the proposed research is to define in monkeys the axonal pathways by which the midbrain periaqueductal gray (PAG) may influence cortical function. The PAG as a critical component in generating emotional expression, and distinct subdivisions of the PAG coordinate distinct emotional reactions to different types of stress. The PAG projects extensively to the midline/intralaminar thalamic nuclei (ILN), which represents one likely pathway through which the PAG may influence cortical function. In rats, individual ILN project to circumscribed areas of the cerebral cortex that correspond to the primate orbital and medial prefrontal cortex (OMPFC), a cortical area thought to be involved in the highest levels of emotional processing. Although these pathways to the cerebral cortex are best known in rats, the OMPFC is much more developed and better known in monkeys. In particular, the primate OMPFC can be divided into distinct functional networks that are hypothesized to subserve different components of emotion. It is hypothesized that the ascending pathways from subdivisions of the PAG will interact differentially with the two networks, reflecting their differential role in emotional reactions to stress. A clear understanding of how this pathway is linked in primates may provide insight into the neural basis of psychiatric illnesses such as major depression and anxiety disorders, which are characterized by maladaptive emotional responses to stress.